Antiseptic compositions

ABSTRACT

COMPOSITIONS POSSESSING ANTIBACTERIAL ACTIVITY THROUGH THE USE OF A SYNERGISTIC MIXTURE OF HEXACHLOROPHENE AND HALOGEN SUBSTITUTED PHENYL 2-EHTYLHEXYL-1-UREAS.

E. JUNGERMANN ETAL ANTISEPTIC COMPOSITIONS March 28, 1972 Filed June 30, 1969 OOm O OmNO m2 WInOtO IU QXMI mod MIC (MINIMUM INHIBITOR) CONCENTRATION) IN PPM IN VE'NTORS N M m L m M HRH G NMM w DA EWO R E EM United States Patent US. Cl. 424322 4 Claims ABSTRACT OF THE DISCLOSURE Compositions possessing antibacterial activity through the use of a synergistic mixture of hexachlorophene and halogen substituted phenyl 2-ethylhexyl-1-ureas.

BACKGROUND OF THE INVENTION Antiseptic or antibacterial agents have been used in soaps and other detergent and cosmetic compositions for a considerable period of time. Prior to World War II, the most widely used materials for such purpose were certain cresol derivatives. Although these cresol derivatives were somewhat effective they tended to impart a strong characteristic odor to the soap which severely limited their use in the consumer soap market. In 1941, Kunz and Gump discovered that certain halogenated bisphenols maintained their antibacterial activity in the presence of soap without imparting any negative qualities. This discovery was subsequently patented under US. 2,535,077. The most promising of the halogenated bisphenols was hexachlorophene[2,2' methylene bis(3,4,6- trichlorophenol)] and it subsequently became widely used in consumer toilet soap products.

Since the discovery by Kunz and Gump, the popularity of antibacterial cleansing compositions such as soap for both laundry and toilet use has increased tremendously. It is now estimated that over 46% of all consumer dollars spent annually in the United States on toilet soap is on antibacterial and deodorant soaps.

Although the past decade has seen major improvements in antibacterial systems for cleansing compositions such as soap, such as the introduction of a number of new antibacterial agents and the introduction of synergistic antibacterial systems, the number of compounds and systems that have been developed and which are suitable from technical, safety and economic points of view is really quite small. In order for an antibacterial agent to become a successful candidate for use in a product such as toilet soap, it must possess a number of properties, such as:

'(l) Broad spectrum antibacterial activity in the presence of soap or other cleansing agent.

(2) Substantivity to the skin.

(3) Effective deodorancy.

(4) Eflicacy in degerming the skin and in the control of certain bacterially caused skin conditions, such as diaper rash, and secondary infections of cuts, scratches and abrasions.

(5) Chemical stability in the presence of the cleansing composition.

(6) Compatibility with the color and odor of the finished product.

(7) Non-reactivity with the other components of the cleansing composition, that is, perfumes, antioxidants, brighteners, etc.

(8) Mildness and safety for general use of the finished product.

(9) Satisfactory economics.

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Relatively few antibacterial agents or bacteriostats have been found to meet all of the above requirements. At the present time the most important commercially used bacteriostats for use in cleansing compositions such as soap are hexachlorophene, TCC (triclocarban), TBS (3,4',5- tribromosalicylanilide) and 4,4 dichloro 3 trifluoromethyl carbanilide. While the above compounds have, in general, excellent properties and are widely used, they all have certain drawbacks. Hexachlorophene is somewhat sensitive to sunlight. The substituted ureas may be unstable in alkali media at elevated temperatures; and, in the case of the halogenated salicylanilides, there have been instances of isolated cases of photodermatitis.

The most significant advance in soap bacteriostats has been the development of synergistic bacteriostatic systems. The term synergistic activity as applied herein means an antibacterial efiect which is greater in combination than the sum of the antibacterial effects of the separate components. Casely and Noel, in US. Pat. 3,177,155, disclose and claim synergistic binary antibacterial systems comprising mixtures of the isomeric trihalogenated carbanilides with a number of halogenated bisphenols and alkylated halogenated bisphenols.

A preferred synergistic combination according to the Casely and Noel US. Pat. 3,177,155 is hexachlorophene and certain of the halogenated carbanilides, particularly triclocarban. The discovery of synergism between the halogenated bisphenols and the halogenated carbanilides was extremely important in that it permitted soap manufacturers and others to provide detergent compositions having a high level of antibacterial activity, but on the other hand, having a greatly reduced concentration of antibacterial agents. The discovery was of further importance because one could then substantially decrease the amount of hexachlorophene employed in the antibacterial composition and thereby greatly reduce the tendency of such compositions to discolor upon prolonged exposure to sunlight.

It has been previously found by others that antibacterial properties are imparted to various compositions by the incorporation therein of halogen substituted phenyl 2- ethylhexyl-l-ureas. In Belgian Pat. 709,240 to Ci-ba Societe Anonyme it is stated that such ureas are effective broad spectrum antibiotics. The preparation of the aforementioned ureas are fully set forth in this Belgian patent.

SUMMARY OF THE INVENTION In accordance with this invention, it has been found that mixtures of [1-(Z-ethylhexyl)-3-(3,5-bis(trifluoromethyl)phenyl)urea] and having the structure NHCNHCHQCIK CH2) on and hexachlorophene exhibit synergistic antibacterial activity and that this activity is maintained unimpaired when such mixtures are incorporated into various detergent compositions such as soap and also in various cosmetic preparations.

It is therefore an object of this invention to provide antibacterial compositions which include as antibacterial agents a synergistic combination of hexachlorophene and halogen substituted phenyl 2-ethylhexyl-1-ureas.

It is a still further Object of this invention to provide antibacterial agents which are effective in soap and in other detergent and cosmetic mediums.

Other objects and advantages and a fuller understanding of our invention will become apparent from the ensuing description and examples.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In a specific embodiment, our invention may be exemplified by a soap composition containing as the active antibacterial ingredient a synergistic mixture of (A) the aforementioned urea and (B) hexachlorophene [2,2'- methylene-bis(3,4,6-trichlorophenol)] and wherein the ratio of A to B present in the soap in parts by weight is from about 22.9 to 1 to about 1 to 19.3..

It is found that when components A and J3 of the synergistic mixture as set forth above are used together, a germicidal effect is achieved which is substantially greater than the mere total of the individual effects of the individual ingredients. This is important in cases where it is desirable to increase the activity of the hexachlorophene ingredient without employing higher concentrations, and in other cases, it assumes an even greater importance from an economic standpoint, since the presence of the halogen substituted phenyl 2-ethylhexyl-1-urea enables a reduction in the total concentration of the antibacterial agent while at the same time retaining the desired level of antibacterial effect.

What the actual mechanism of the potentiating or synergistic effect is, we cannot explain. The invention relates to the synergistic cooperation of these three agents when used in minor proportions in various compositions, especially detergent compositions such as soap, and the discovery that this synergistic phenomenon occurs even at the high pH conditions existing in soap and other detergent formulations.

Relatively small amounts of the components of our synergistic mixture are sufiicient for the increased antibacterial effect. Satisfactory results can be obtained when the combined Weights of the above two agents are from .10% to 5.0% of the total weight of the composition. A preferred range is the weight concentration of about 1.0% to 2.5%. It should be understood that even concentrations below the ranges set out above will provide some degree of antibacterial effect and a substantially higher concentration than those referred to will also give satisfactory results, although there are certain practical considerations such as the cost of the agents which limits the desirability of greater amounts of the germicidal composition in the soap or other medium.

As indicated above, the ratio of the urea to the hexachlorophene is from about 22.9 to 1 to about 1 to 19.3 (parts by weight).

The term soap refers to the water-soluble ammonium, metallic, or organic base salts of various fatty acids, which are chiefly lauric, oleic, stearic, and palmitic acids. As used in this description, the term is intended to cover all products in which soap is a major constituent, for example, bar, flake, powdered, soft and liquid soaps; shaving creams, toothpaste, cleansing creams, etc.

The anionic type and nonionic type synthetic detergents can be used in place of the soap. The anionic type synthetics suitable for use in the invention can be described as those detergents having pronounced cleansing power and including in their molecular structure an alkyl radical containing from 6 to 18 carbon atoms and a sulfonic acid or sulfuric acid ester radical. Either organic base, ammonium, sodium or potassium salts of the anionic type detergents can be used. The main types 'of detergents falling within this category are alkyl-aryl sulfonates, such as sodium or potassium dodecyl benzene sulfonate, sodium or potassium octadecyl benzene sulfonate, and sodium or potassium octyl naphthalene sulfonate; the alkyl sulfates, such as sodium or potassium salts of dodecyl, hexadecyl, and octadecyl sulfates; the sulfonated fatty acid amides, such as sodium or potassium salts of the oleic acid amide of methyl taurine; and the sulfonated monoglycerides 4 such as the mono-coconut oil fatty acid ester of sodium 1,2-hydroxypropane-3-sulfonate.

The nonionic type synthetic detergents suitable for use in the invention may be described as those detergents which do not ionize in solution but owe their water-solubility to unionized polar groups such as oxyethyl or other linkages. The main types of detergents falling within this category are the polyoxyethylene ethers of the higher fatty alcohols and alkyl phenols; the polyethylene glycols of fatty acids; fatty alkylol amide condensation products; polymers of ethylene and propylene oxides; compounds formed by the addition of propylene oxide to ethylene diamine, followed by the addition of ethylene oxide; fatty acid ethylene oxide condensation products; condensation products of ethylene oxide and a fatty acid ester of a polyhydric alcohol or sugar; and the detergents prepared by heating together a higher fatty acid with a diethanolamine. Some examples of synthetic nonionics suitable for the purpose of this invention are ethylene oxide-tall oil fatty acid reaction products; isooctyl phenol-ethylene oxide reaction products; propylene oxide-ethylene oxide reaction products; and combinations of isooctyl phenol-ethylene oxide with coconut oil fatty acid ethylene oxide reaction products.

The synergistic combination of [1-(2-ethylhexyl)-3- (3,5-bis(trifiuoromethyl)phenyl)urea] and hexachlorophene can be added to the soap and other detergents by any suitable method which results in a uniform distribution of the agents throughout the entire mass.

Specific examples illustrating our invention are set out as follows:

EXAMPLE I A convenient and meaningful method of measuring the antibacterial effectiveness of various agents is by means of a modified agar: streak method utilizing a 10% soap solution (100,000 p.p.m. of soap) containing the various test agents. Briefly the test consists of making serial dilutions of the following solution: 10 ml. of a solution containing 0.7% of the urea and 1.5% of hexachlorophene in dirnethylformamide were dispersed into ml. of distilled water containing 10 grams of soap. All solutions are maintained at 60 C. until they are dispensed. Aliquots of the dilutions containing concentrations of the bacteriostatic agents ranging from about 0.02 to 10 p.p.m. are dispensed into measured amounts of nutrient agar at 50 C. and thoroughly dispersed. Plates are poured, allowed to solidify and streaked with a standard 4 mm. loopfiul of a 24-hour broth culture of Staphylococcus aureus FDA 209. After incubation for 24 hours at 37 C. the bacteriostatic end point is determined. The bacteriostatic end point, hereinafter called the minimum inhibitory concentration (MIC), represents the minimum concentration in p.p.m. of the bacteriostatic agent necessary to inhibit all growth of the inoculent organism. No particular minimum inhibitory concentration has been established to determine the usefulness of a bacteriostatic agent, although the lower the end-point, the better the bacteriostatic activiy and the smaller the amount of the agent necessary to maintain a particular degree of effectiveness. The soap utilized for these evaluations was a neutral white toilet soap containing about 20% by weight sodium coco soap and 80% by weight sodium tallow soap.

Using the modified agar streak method as set forth above it was determined that a soap solution containing 0.70% of the [l-(Z-ethylhexyl) 3 (3,5-bis(trifiuoromethyl)phenyl)urea] had an end point or MIC of 0.20 p.p.m. It was also determined that a soap solution containing 1.50% of hexachlorophene had an end point of 0.20 p.p.m. Various proportions of the above solutions were combined to give mixtures that would be expected to give an end point or MIC of 0.20 p.p.m., if no synergistic activity took place. In the following table, there is set forth the MIC of varying ratios of the substituted urea and hexachlorophene.

Parts of a 0,70% substi- Parts of a 1.50% Percent tuted urea 1 hexachlorophene substitute d hexachloro- Percent Ratio of substituted urea 1 to MIC (P-D-m.) Versus S. aureus solution solution urea phone hexachlorophene 100 0. 700 None m :1 98 2 0. 686 0. 030 22. 9: 1 95 5 0. 665 0. 075 8. 9: 1 90 10 0. 630 0. 150 4. 2: 1 80 0.660 0.300 1. 9: 1 70 0. 490 0. 450 1. 1: 1 60 0. 420 0. 600 1:1. 4 5O 0. 350 0. 750 1:2. 1 4O 0. 280 0. 900 1:3. 2 30 0. 210 1. 050 1:5. 0 20 0. 140 1. 200 1:8. 6 10 O 070 1.350 1:19.3 0 None 1. 500 1: m

Norm-Tested at 0.05, 0.10, 0.14, 0.16, 0.18, 0.20, 0.22, 0.24, 0.20 and 0.50 p.p.m.

The results as set forth in the above table have been 20 ethylhexyl)-3-(3,5-bis(trifluoromethyl)phenyl)urea [haloreproduced in graph form on the attached drawing. In the graph the MICs (ordinate) have been plotted against the concentration (abscissa). Line A represents the expected MIC if the activity of the two agents were merely additive. The curved line B represents the actual MICs of a combination of the two agents at varying proportions. That portion of line B lying between points 0 and D represents the region in which unexpected or synergistic activity takes place. Thus, there is synergism when the ratio of the substituted urea to hexachlorophene (parts by weight) is from about 22.9 to 1 to about 1 to 19.3.

The results set forth in the foregoing example with respect to a specific soap (20% sodium coco and 80% sodium tallow soap) are obtained with soaps generally. Thus, a fatty acid soap such as sodium laurate, potassium stearate, sodium oleate, and potassium myristate will also produce these results. Furthermore, the synergistic action is independent of the soap medium and will take place in non-detergent media as well as in anionic detergents other than soap and in nonionic systems. At the same time, soap is a system in which the synergistic components are highly eifective and useful.

While this invention has been described in and exemplified in terms of its preferred embodiments, those skilled in the art will appreciate that variations can be made without departing from the spirit and scope of the invention.

What is claimed is:

1. Antibacterial compositions consisting essentially of a synergistic combination of hexachlorophene and 1-(2- gen substituted phenyl Z-ethylhexyl-l-urea] wherein the ratio of said urea to said hexachlorophene in parts by weight is from about 22.9 to 1 to about 1 to 19.3.

2. Antibacterial compositions according to claim 1 wherein the total concentration of said hexachlorophene and urea is from about .10% to about 5.0% by weight of the composition.

3. Antibacterial compositions according to claim 1 which contain a cleansing composition selected from the group consisting of water-soluble soap, anionic synthetic detergent and noni'onic synthetic detergent.

4. The antibacterial compositions of claim 3 wherein the cleansing composition is a water-soluble soap.

References Cited UNITED STATES PATENTS 2,535,077 12/1950 Kunz et a1. 252107 3,084,097 4/1963 Reller et a1 252106 X 3,276,955 10/1966 Casely et a1 252106 X HERBERT B. GUYNN, Primary Examiner P. E. WILLIS, Assistant Examiner U.S. Cl. X.R. 

